Tuberculosis (TB) is mostly a pulmonary lung disease caused by Mycobacterium tuberculosis (Mtb). This organism is a slow-growing bacillus that is transmitted by the respiratory route. Soon after infection, the bacilli penetrate alveolar macrophages and survive within early phagosomes. Innate immune responses directed by macrophages predominate early in the infection. Subsequent recruitment of dendritic cells leads to cell-mediated responses involving CD4+ and CD8+ T cells and eventually to granuloma formation. Among infectious diseases, tuberculosis remains the second leading killer of adults in the world, with more than 2 million TB-related deaths each year (CDC 2004). The vast majority of immunocompetent individuals are able to contain, but not eliminate, the pathogen in pulmonary granulomas, leading to latent tuberculosis infection a small minority of cases, through unclear mechanisms, persistent bacilli can reactivate to produce disease many years to decades after initial infection.
Virulent Mycobacterium Cell Wall-associated Lipoglycans
A major cell surface component of Mtb and other virulent Mycobacterium sp. is the polysaccharide mannosylated lipoarabinomannan (ManLAM). ManLAM is a phosphatidylinositol-anchored lipoglycan composed of a mannan core with oligoarabinosyl-containing side-chains with diverse biological activities. This polysaccharide accounts for up to 5 mg g −1 bacterial weight. ManLAM structure differs according to mycobacterial species, and three general classes of LAM have been described: (i) ManLAM, from the virulent strains Erdman and H37Rv and the avirulent strains H37Ra and BCG [Chatterjee, D., et al. J Biol Chem 267: 6234-6239 (1992); Prinzis, S., et al. J Gen Microbiol 139: 2649-2658 (1993)], which is characterized by extensive mannose capping of the arabinan termini; (ii) phospho-myo-inositol-capped LAM (PILAM), found in the rapidly growing mycobacteria M. smegmatis and M. fortuitum [Nigou, J. Biochimie 85:153-166 (2003)]; and (iii) AraLAM, which was described in the rapidly growing M. chelonae and lacks mannosylation in its arabinan termini [Guerardel, Y., et al. J Biol Chem 277:30635-30648 (2002)]. Although there is significant heterogeneity between LAM molecules with respect to glycosylation and acylation [Nigou et al. (2003) ibid.], differences in biological activity between the major classes of LAM have been attributed primarily to the heavy mannose capping of ManLAM [Chatterjee et al. (1992). ibid.]
In several publications it has been shown that sera of TB patients contain higher levels of anti-ManLAM antibodies than that of healthy individuals [Hetland G, et al. Clin Diagn Lab Immunol. 5(2):211-8 (1998)]. Consequently it has been suggested to be one of the candidate antigens for rapid diagnosis of TB [Antunes A, et al. Res Microbiol. 153(5):301-5 (2002)].
LAMs that are surface components have been suggested as target molecules for an efficient vaccine candidate due to its presence on the bacterial surface [Glatman-Freedman A, FEMS Immunol Med Microbiol. 39(l):9-16 (2003)] Nonetheless, purified ManLAM was found to be a poor immunogen [Hamasur B, et al., Vaccine 16:17(22):2853-61 (1999)]. It has been suggested to conjugate mycobacterial polysaccharides to a carrier protein [Glatman-Freedman A, (2003) ibid.].